This Center for Medications Development (MDU) has a theme of cocaine pharrnacotherapy with eight outpatient randomized clinical trials in four comorbid populations: depressed, opioid dependent (methadone and LAAM), and those with brain perfusion defects. These eight trials are arranged sequentially with four during months 1 to 30 (trials #1,3,5,7) and four during months 31-60 (trials #2,4,6,8). Trials 1 and 2 are "Bupropion & sertraline for depression and cocaine dependence" including 60 patients each in randomized, placebo controlled 12 week trials - bupropion (#1) and sertraline (#2). Trials 3 and 4 are "Disulfiram & GABA agonists with LAAM for cocaine" including 60 patients in randomized, placebo controlled 12 week trials of first disulfiram (#3) and then one of the GABA agents tiagabine or baclofen (#4). Trial 5 in methadone patients will involve tiagabine and baclofen in an 8 week screening study that allocates 60 subjects to five cells including placebo and two doses of each agent during the first 30 months. Trial 6 uses a similar screening design involving glutamate antagonists - acamprosate and lamotrigine in months 31-60. Trials 7 and 8 are "Clopidogrel & isradipine for brain perfusion defects" involving blood flow neuroimaging in two different groups of 60 patients with these cocaine-induced defects as an outcome. These 12 week trials of first clopidogrel (#7) and then isradipine (#8) include 4 weeks residential with an 8 week outpatient follow-up. Overall, about 500 patients will be studied in this Center and nine different agents in either screening (trials 5 & 6) or full Phase ll trials.